Methods of treatment of chronic pain using eszopiclone

ABSTRACT

The invention relates to the use of eszopiclone for the treatment of low-level, chronic pain and fatigue associated with pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority from U.S. provisional application60/559,590, filed Apr. 5, 2004, the entire disclosure of which isincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to the use of eszopiclone for the treatment ofchronic pain.

BACKGROUND OF THE INVENTION

Eszopiclone is a cyclopyrrolone that has the chemical name (+)6-(5-chloropyrid-2-yl)-5-(4-methylpiperazin-1-yl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3-4-b]pyrazineor (+)6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl4-methylpiperazine-1-carboxylate. The chemical structure of eszopicloneis shown below:

Eszopiclone is the S-(+)-optical isomer of the compound zopiclone, whichis described in U.S. Pat. Nos. 6,319,926 and 6,444,673, and in Goa andHeel, [Drugs, 32:48-65 (1986)] and in U.S. Pat. Nos. 3,862,149 and4,220,646. This isomer, which will hereinafter be referred to by itsUSAN-approved generic name, eszopiclone, includes the optically pure andthe substantially optically pure (e.g., 90%, 95% or 99% optical purity)S-(+)-zopiclone isomer.

Zopiclone was the first of a chemically distinct class of hypnotic andanxiolytic compounds that offers a psychotherapeutic profile of efficacyand side effects similar to the benzodiazepines. This class ofcompounds, the cyclopyrrolones, appears to cause less residual sedationand less slowing of reaction times than the benzodiazepines, and itoffers the promise of an improved therapeutic index overbenzodiazepines.

The pharmacology of zopiclone has been shown both preclinically andclinically to be characterized by several elements. It is predominantlya hypnotic-sedative, offering significant activity on first treatmentwithout concomitant respiratory or cardiac depression. The compoundbinds to the benzodiazepine receptor complex, or to a site linkedclosely to this receptor complex. (See Goa, K. L. and Heel, R. C. Drugs,32:48-65, (1986); Brun, J. P., Pharmacology, Biochemistry and Behavior,60 29:831-832, (1988); Julou, L. et al., Pharmacology, Biochemistry andBehavior, 23:653-659, (1985); Verma, A. and Snyder S. H., Ann. Rev.Pharmacol. Toxicol, 29:307-322, (1989). The central benzodiazepinereceptor is a macromolecular complex that includes a site for thebinding of gamma-aminobutyric acid (GABA), the inhibitoryneurotransmitter, suggesting that benzodiazepines and chemicallyunrelated agonists including zopiclone may exert their effects byfacilitating the synaptic effects of GABA. While it interacts with thebenzodiazepine receptor, zopiclone apparently has minimal effects onmemory, no interaction with alcohol, and little or no abuse ordependence potential. The drug is well absorbed from the stomach, and itis not highly bound to plasma proteins. The racemic mixture, zopiclone,has been in use for some years primarily as a hypnotic, and recently theUSFDA approved use of eszopiclone (LUNESTRA™) for the treatment ofinsomnia.

SUMMARY OF THE INVENTION

The invention relates to methods of treating chronic pain witheszopiclone.

Thus, the invention relates to treating low-level, chronic paincomprising administering to a patient a therapeutically effective amountof eszopiclone.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to methods of treating chronic pain witheszopiclone. The S-(+)-zopiclone has an enantiomeric excess (e.e.)greater than 90%. It may be administered parenterally, transdermally ororally, preferably in an amount of 0.5 mg to 15 mg per day. Inparticular embodiments the eszopiclone is administered at 0.5 mg, 1.0mg, 2.0 mg and 3.0 mg per day and in 0.5 mg, 1.0 mg, 2.0 mg and 3.0 mgper dosage.

It has now been discovered that eszopiclone is useful for treatinglow-level, chronic pain. While acute pain is a normal sensationtriggered in the nervous system to alert an organism to possible injury,chronic pain persists. Pain signals keep firing in the nervous systemfor weeks, months, even years. There may have been an initialmishap—sprained back, serious infection, or there may be an ongoingcause of pain—arthritis, cancer, ear infection, but some people sufferchronic pain in the absence of any past injury or evidence of bodydamage. Many chronic pain conditions affect older adults. Common chronicpain complaints include headache, low back pain, cancer pain, arthritispain, neurogenic or neuropathic pain (pain resulting from damage to theperipheral nerves or to the central nervous system itself), psychogenicpain (pain not due to past disease or injury or any visible sign ofdamage inside or outside the nervous system). The pain for whicheszopiclone is best suited is neuropathic pain or pain associated withrheumatoid arthritis, osteoarthritis, muscle spasm, spasticity orfibromyalgia.

Neuropathic pain arises from disorders that include, but are not limitedto, thoracic outlet obstruction syndromes, compression and entrapmentneuropathies such as ulnar nerve palsy, carpel tunnel syndrome, peronealnerve palsy, and radial nerve palsy; Guillain-Barré syndrome; painassociated with or resulting from: trauma caused by injury or surgicaloperation; tumors; bony hyperostosis, casts; crutches; prolonged crampedpostures; hemorrhage into a nerve; exposure to cold or radiation;collagen-vascular disorders; metabolic disorders, such as diabetes,hypothyroidism, porphyria, sarcoidosis, amyloidosis, and uremia;infectious diseases such as Lyme disease and HIV; toxins, such asemetine, hexobarbital, barbital, chorobutanol, sulfonamides, phenytoin,nitrofurantoin, the vinca alkaloids, heavy metals, carbon monoxide,triorthocresylphosphate, orthodinitrophenol, and other solvents andindustrial poisons; autoimmune reactions; nutritional deficiency, andvitamin B deficiency.

The effect of eszopiclone on pain may be direct, as a result of itsaction on benzodiazepine receptors, or indirect, as a result of itseffect on sleep. The direct analgesic effects of eszopiclone weredemonstrated in a clinical study presented in Example 1.

In a related aspect eszopiclone is useful for treating fatigueassociated with pain.

The pharmacologic profile of hypnotic-sedative, anxiolytic agents of thebenzodiazepine class has been rather well established (Goodman andGilman: The Pharmacological Basis of Therapeutics, 7th. Edition, Chapt.17, 340-351, (1985), MacMillan Publishing Co., N.Y.) and has beenextended to non-benzodiazepine agents of the cyclopyrrolone class(Bardone, M. C. et al., Abstract No. 2319, 7th. Int. Congr. Pharm.Paris, July, 1978, Pergamon Press, London; Julou, L. et al.,Pharmacology, Biochemistry and Behavior, 23:653-659 (1985)).Accordingly, a variety of experimental models, which are rather wellcharacterized (Julou, L. et al., ibid, 1985) can be used to characterizethe various activities of eszopiclone. The acute toxicity of apharmaceutical composition comprising zopiclone can be determined instudies in which rats are administered at progressively higher doses(mg/kg) of pharmaceutical composition. That lethal dose which, whenadministered orally, causes death of 50% of the test animals, isreported as the LD₅₀.

To establish the safety of eszopiclone, a dose escalation study wascarried out. Cardiovascular and respiratory parameters were evaluated inconscious dogs following acute intravenous administration of (R)-, (S)-or racemic zopiclone at three doses (3, 5 and 12 mg/kg). Blood gases andblood chemistries (pH, pCO2, pO2, hematocrit, and lactate) remainedunaffected in all dose groups. No evidence of cardiotoxicity, asevidence by the electrocardiogram (ECG), was observed followingadministration of racemic zopiclone or its enantiomers. Racemiczopiclone and eszopiclone produced dose dependent, transient decreasesin blood pressure with an accompanying compensatory increase in heartrate, whereas (R) zopiclone had no effect. Administration of the highestdose (12 mg/kg) of racemic and (S)-zopiclone produced a more pronouncedhypotensive effect (30-40% decrease from baseline). Complete recoverywas not evident during the observational period. However, the valueswere returning toward baseline throughout the observation period.(R)-Zopiclone did not produce a consistent hemodynamic effect following12 mg/kg.

Eszopiclone was evaluated for antimuscarinic activity in vivo. Theracemate did not produce mydriasis in mice at any of the doses tested(maximum dose=100 mg/kg, p.o.). In another in vivo assay, neither (R)-,(S)-, nor racemic zopiclone significantly antagonized oxotremorineinduced salivation in mice at doses up to 300 mg/kg, p.o. These resultssuggest that eszopiclone does not produce antimuscarinic effects and areconsistent with eszopiclone's lack of in vitro affinity for muscarinicreceptors.

All these studies point to little or no actions on the cardiovascularsystem or on the autonomic or peripheral nervous systems. Thus the drugappears to have a high safety margin with no indication of deleteriousperipheral effects.

As used herein, and as would be understood by the person of skill in themedical art, to which the invention pertains, the recitation of theterms “eszopiclone” and “S-(+)-zopiclone” include pharmaceuticallyacceptable salts, hydrates, solvates, clathrates, and polymorphs ofS-(+)-zopiclone. The term “pharmaceutically acceptable salt” refers tosalts prepared from pharmaceutically acceptable non-toxic acids or basesincluding inorganic acids and bases and organic acids and bases. Saltsmay be prepared from pharmaceutically acceptable non-toxic acidsincluding inorganic and organic acids. Suitable pharmaceuticallyacceptable acid addition salts for the compounds of the presentinvention include acetic, benzenesulfonic (besylate), benzoic,camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic,hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric,succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like. Theterm “solvate” refers to a compound—in this case eszopiclone—in thesolid state, wherein molecules of a suitable solvent are incorporated inthe crystal lattice. A suitable solvent for therapeutic administrationis physiologically tolerable at the dosage administered. Examples ofsuitable solvents for therapeutic administration are ethanol and water.When water is the solvent, the solvate is referred to as a hydrate. Ingeneral, solvates are formed by dissolving the compound in theappropriate solvent and isolating the solvate by cooling or using anantisolvent. The solvate is typically dried or azeotroped under ambientconditions.

The term “preventing” as used herein refers to administering amedicament beforehand to forestall or obtund an attack. The person ofordinary skill in the medical art (to which the present method claimsare directed) recognizes that the term “prevent” is not an absoluteterm. In the medical art it is understood to refer to the prophylacticadministration of a drug to substantially diminish the likelihood orseriousness of a condition, and this is the sense intended inapplicants' claims. The term “treating” includes prophylaxis as well asthe amelioration of the acute symptoms. Note that “treating” refers toeither or both of the amelioration of symptoms and the resolution of theunderlying condition. In many of the conditions of the invention, theadministration of eszopiclone may act not directly on the disease state,but rather on some pernicious symptom, and the improvement of thatsymptom leads to a general and desirable amelioration of the diseasestate.

As used herein, the recitation of the terms “eszopiclone” and“S-(+)-zopiclone” refers to eszopiclone having an enantiomeric excess(e.e.) greater than 90%. The term “enantiomeric excess” is well known inthe art and is defined for a resolution of ab into a${{+ b}\quad{as}\quad{ee}_{a}} = {\left( \frac{{{{conc}.\quad{of}}\quad a} - {{{conc}.\quad{of}}\quad b}}{{{{conc}.\quad{of}}\quad a} + {{{conc}.\quad{of}}\quad b}} \right) \times 100}$

The term “enantiomeric excess” is related to the older term “opticalpurity” in that both are measures of the same phenomenon. The value ofee will be a number from 0 to 100, zero being racemic and 100 beingpure, single enantiomer. A compound which in the past might have beencalled 98% optically pure is now more precisely described as 96% ee.; inother words, a 90% e.e. reflects the presence of 95% of one enantiomerand 5% of the other in the material in question. In the case ofeszopiclone, e.e. of greater than 95% is preferred; e.e. of greater than98% is more preferred; and e.e. of greater than 99% is most preferred.

Racemic zopiclone is commercially available and can be made usingvarious methods, such as those disclosed in U.S. Pat. Nos. 3,862,149 and4,220,646. Eszopiclone is also commercially available or it may beprepared from racemic zopiclone using standard methods, such aschiral-phase chromatography, resolution of an optically active salt,stereoselective enzymatic catalysis by means of an appropriatemicroorganism, or asymmetric synthesis. U.S. Pat. No. 6,319,926discloses methods for making (+) zopiclone, including resolution fromracemic zopiclone by means of an optically active acid, such asD(+)-O,O′-dibenzoyltartaric acid.

Another method for making Eszopiclone is by synthesis from racemiczopiclone (or (RS)-zopiclone) by chemical resolution via the D-malatesalt as shown in the following synthesis schematic.

In the synthetic route shown above, (RS)-zopiclone and D-malic acid aredissolved in a mixture of acetone and methanol to form (S)-zopicloneD-malate and (R)-zopiclone D-malate. The two diastereomeric salts areresolved in-situ by selective crystallization, filtration and rinsing toproduce highly (S)-enriched zopiclone D-malate salt. In this process,the majority of (R)-zopiclone D-malate remains in the mother liquors. Inthis method, the use of an acetone/methanol co-solvent system results ina highly diastereoselective salt crystallization, and preferably, theco-solvent ratio used should be in the range of approximately 1.9/1 to2.3/1 w/w acetone in methanol. Preferably, this stage of the process mayalso include cooling the reaction mixture during the isolation step to atemperature in the inclusive range of about 10° C. to 15° C., andwashing or rinsing the wet cake obtained after filtration with coldsolvent, such as cold methanol.

The resulting (S)-zopiclone D-malate salt is converted to optically pure(S)-zopiclone free base by treatment with aqueous potassium carbonateand ethyl acetate, followed by phase separation and crystallization. Inthis process, once a solution of (S)-zopiclone free-base is obtained,additional enantiomeric enrichment (typically 1 to 4%) can be achievedby crystallization from ethyl acetate of low water content. The watercontent can be controlled, e.g., by azeotropic distillation, andincorporating an in-process control of water content into thecrystallization process can further improve the robustness ofenantiomeric purity. Preferably, the water level during this step is 2%or less, more preferably 1% or less, and most preferably 0.6% or less.The resulting optically pure eszopiclone free base can then be milled toa desired size for use as an active ingredient in a pharmaceuticalcomposition according to the present invention. These compositions areuseful in treating disorders that are affected by the binding ofagonists to central nervous system and peripheral benzodiazepinereceptors while avoiding the adverse effects associated with theadministration of the racemic mixture of zopiclone.

The size of a prophylactic or therapeutic dose of eszopiclone in theacute or chronic management of disease will vary with the severity ofthe condition to be treated and the route of administration. The dose,and perhaps the dose frequency, will also vary according to the age,body weight, and response of the individual patient. In general, thetotal daily dose ranges, for the conditions described herein, is fromabout 0.5 mg to about 15 mg. Preferably, a daily dose range should bebetween about 0.5 mg to about 12.5 mg. Most preferably, a daily doserange should be between about 2.0 mg to about 10.0 mg. In managing thepatient, the therapy may be initiated at a lower dose, perhaps about 0.5mg to about 7.5 mg and increased up to about 10 mg or higherdepending-on the patient's global response. It is further recommendedthat children and patients over 65 years, and those with impaired renalor hepatic function, initially receive low doses, and that they betitrated based on global response and blood level. It may be necessaryto use dosages outside these ranges in some cases.

Pharmaceutical compositions of the present invention may be administeredby any suitable route of administration that provides a patient with atherapeutically effective dosage of eszopiclone. Typically, theeszopiclone pharmaceutical compositions described herein will beformulated for oral administration or for inhalation. Suitable dosageforms include tablets, troches, cachets, caplets, capsules, includinghard and soft gelatin capsules, and the like. Tablet forms, however,remain a preferred dosage form because of advantages afforded both thepatient (e.g., accuracy of dosage, compactness, portability, blandnessof taste and ease of administration) and to the manufacturer (e.g.,simplicity and economy of preparation, stability and convenience inpackaging, shipping and dispensing).

The pharmaceutical compositions may further include a “pharmaceuticallyacceptable inert carrier” and this expression is intended to include oneor more inert excipients, which include starches, polyols, granulatingagents, microcrystalline cellulose, diluents, lubricants, binders,disintegrating agents, and the like. If desired, tablet dosages of thedisclosed compositions may be coated by standard aqueous or nonaqueoustechniques. In one embodiment, coating with hydroxypropylmethylcellulose(HPMC) is employed. “Pharmaceutically acceptable carrier” alsoencompasses controlled release means. Compositions of the presentinvention may also optionally include other therapeutic ingredients,anti-caking agents, preservatives, sweetening agents, colorants,flavors, desiccants, plasticizers, dyes, and the like. However, any suchoptional ingredient must be compatible with eszopiclone to insure thestability of the formulation.

In the case where an oral composition is employed, a suitable dosagerange for use is from about 0.5 mg to about 15.0 mg. Preferably, a doserange of between about 0.5 mg to about 12.5 mg is given as a once dailyadministration or in divided doses if required; most preferably, a doserange of from about 0.5 mg to about 10 mg is given, either as a oncedaily administration or in divided doses if required. Patients may beupward titrated from below to within this dose range to a satisfactorycontrol of symptoms as appropriate.

Capsule Formulation mg per mg per mg per mg per capsule capsule capsulecapsule formulation formulation formulation formulation ingredient A B CD Eszopiclone 0.5 1.0 2.0 3.0 lactose 79 78.5 77.5 76.5 corn starch 2020 20 20 magnesium 0.5 0.5 0.5 0.5 stearate total weight 100 100 100 100The active ingredient, eszopiclone, lactose, and corn starch are blendeduntil uniform; then the magnesium stearate is blended into the resultingpowder. The resulting mixture is encapsulated into suitably sizedtwo-piece hard gelatin capsules.

Tablet Formulation mg per mg per mg per mg per tablet tablet tablettablet formulation formulation formulation formulation ingredient A B CD Eszopiclone 0.5 1.0 2.0 3.0 lactose 153 152.5 151.5 150.5 corn starch30 30 30 30 pre-gelatinized 15 15 15 15 corn starch magnesium 1.5 1.51.5 1.5 stearate compression 200 200 200 200 weight

The active ingredient, eszopiclone, is sieved through a suitable sieveand blended with lactose, starch, and pregelatinized cornstarch.Suitable volumes of purified water are added and the powders aregranulated. After drying, the granules are screened and blended with themagnesium stearate. The granules are then compressed into tablets using7 mm diameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to lactose or the compression weight and using punchesto suit. In one embodiment, eszopiclone is formulated as film-coatedtablets for oral administration containing the following inactiveingredients: calcium phosphate, colloidal silicon dioxide,croscarmellose sodium, hypromellose, lactose, magnesium stearate,microcrystalline cellulose, polyethylene glycol, titanium dioxide,triacetin and optionally FD&C Blue #2.

EXAMPLE 1 Clinical Study on Treatment of Chronic Pain with Eszopiclone

The study was aimed at observing the effect of eszopiclone 3 mg comparedto placebo on daytime function in subjects with insomnia related torheumatoid arthritis. The study was a multicenter, randomized,double-blind, placebo controlled, parallel group study. The study had aone-week single-blind placebo run-in period, followed by four weeks ofdouble blind treatment, and one week of single blind placebo wash-out.

A total of 153 subjects were randomized. Among them, 77 received 3 mg ofeszopiclone (ESZ) nightly (at bedtime) for four weeks and 76 receivedmatching placebo (PBO). The discontinuation rates were low, 5.2% in theESZ group and 9.2% in the PBO group. The patient population waspredominantly female (87%) and Caucasian (84%). Mean age was 52, with arange of 27-64. Subjects had a diagnosis of rheumatoid arthritis (asdefined by the American College of Rheumatology) and were on stabledoses of chronic rheumatoid arthritis medications for a minimum of 90days prior to start of the single-blind placebo run-in period. Inaddition, subjects had insomnia symptoms including wake time after sleeponset (WASO) of >45 minutes, and total sleep time≦6.5 hours. Diagnosisof rheumatoid arthritis predated the onset of insomnia symptoms.

During the double blind treatment, subjects were dosed with 3 mgeszopiclone (ESZ) or matching placebo (PBO) nightly (at bedtime) forfour weeks. Data was analyzed with one-sided significance tests.

Eszopiclone had a significant effect on the change from baseline to endof study (Week 4) in the Overall score for the Arthritis Self-EfficacyScale (the scale is made publicly available by Stanford PatientEducation Research Center, 1000 Welch Road, Suite 204, Palo Alto, Calif.94304). The Pain subscale had a statistically significant difference,both when analyzed alone or in combination with Other Symptoms. SeeTable 1. TABLE 1 Arthritis Self-Efficacy Scale (Intent-to-TreatPopulation) Placebo Eszopiclone 3 mg Observed Change from ObservedChange from Scale Visit (Week) Statistic Value Baseline Value BaselineOverall 3 (Baseline) N 75 77 Mean (SD) 121.6 (39.8) 119.4 (40.9) 25thPercentile 90.0 88.0 Median 124.0 120.0 75th Percentile 156.0 146.0Minimum, 36.0, 186.0 34.0, 200.0 Maximum 5 (Week 4) N 75 75 77 77 Mean(SD) 124.3 (39.7) 2.7 (30.1) 130.9 (38.2) 11.5 (29.3) 25th Percentile92.0 −13.0 103.0 −1.6 Median 131.0 −1.0 132.6 12.0 75th Percentile 160.019.0 162.5 26.0 Minimum, 38.0, 186.0 −83.0, 83.0 27.0, 189.0 −74.0,124.0 Maximum p-value vs. 0.1593 placebo [1] Least Squares 2.4 (3.2)10.4 (3.2) Means (SE) [2] p-value vs. 0.0387 placebo [2] 6 (EOS) N 69 6974 74 Mean (SD) 131.4 (37.3) 9.0 (23.2) 134.5 (35.9) 14.0 (30.5) 25thPercentile 109.0 −9.0 111.0 −3.0 Median 135.0 3.0 133.0 12.5 75thPercentile 160.0 23.0 163.0 32.0 Minimum, 44.0, 198.0 −25.0, 94.0 50.0,193.0 −89.0, 84.0 Maximum p-value vs. 0.4285 placebo [1] Least Squares8.8 (2.9) 12.4 (2.9) Means (SE) [2] p-value vs. 0.1839 placebo [2] Pain3 (Baseline) N 75 77 Mean (SD) 26.4 (9.6) 26.0 (11.5) 25th Percentile19.0 17.0 Median 26.0 26.0 75th Percentile 33.0 34.0 Minimum, 7.0, 44.08.0, 50.0 Maximum 5 (Week 4) N 75 75 76 76 Mean (SD) 25.9 (9.7) −0.4(10.4) −29.3 (9.9) 3.3 (10.5) 25th Percentile 17.0 −6.0 22.0 −1.0 Median26.0 −1.0 28.0 3.0 75th Percentile 33.0 5.0 38.0 10.5 Minimum, 8.0, 49.0−23.0, 34.0 8.0, 50.0 −37.0, 30.0 Maximum p-value vs. 0.0150 placebo [1]Least Squares −0.5 (1.0) 3.1 (1.0) Means (SE) [2] p-value vs. 0.0053placebo [2] 6 (EOS) N 68 68 73 73 Mean (SD) 28.3 (9.4) 2.1 (8.4) 29.2(9.8) 2.7 (10.5) 25th Percentile 21.0 −2.0 22.0 −4.0 Median 27.0 1.030.0 2.0 75th Percentile 35.0 5.0 37.0 8.0 Minimum, 8.0, 48.0 −18.0,32.0 9.0, 49.0 −20.0, 35.0 Maximum p-value vs. 0.3489 placebo [1] LeastSquares 2.0 (1.0) 2.4 (0.9) Means (SE) [2] p-value vs. 0.3668 placebo[2] Function 3 (Baseline) N 75 77 Mean (SD) 58.9 (22.5) 57.2 (22.5) 25thPercentile 42.0 38.0 Median 60.0 59.0 75th Percentile 80.0 77.0 Minimum,9.0, 90.0 12.0, 90.0 Maximum 5 (Week 4) N 75 75 76 76 Mean (SD) 61.0(23.8) 2.1 (14.3) 62.0 (22.1) 4.8 (15.7) 25th Percentile 42.0 −7.0 45.5−1.0 Median 66.0 0.0 61.0 4.0 75th Percentile 81.0 12.0 83.5 13.5Minimum, 9.0, 90.0 −33.0, 45.0 13.0, 90.0 −34.0, 74.0 Maximum p-valuevs. 0.4189 placebo [1] Least Squares 1.9 (1.7) 4.2 (1.7) Means (SE) [2]p-value vs. 0.1697 placebo [2] 6 (EOS) N 68 68 73 73 Mean (SD) 63.8(22.0) 5.1 (11.1) 64.1 (20.5) 6.8 (15.6) 25th Percentile 51.0 −1.0 45.0−1.0 Median 66.5 2.0 65.0 5.0 75th Percentile 81.5 9.5 85.0 14.0Minimum, 10.0, 90.0 −21.0, 42.0 23.0, 90.0 −45.0, 58.0 Maximum p-valuevs. 0.5620 placebo [1] Least Squares 5.0 (1.6) 6.2 (1.6) Means (SE) [2]p-value vs. 0.2909 placebo [2] Other 3 (Baseline) N 73 75 Symptoms Mean(SD) 36.9 (12.8) 36.2 (13.6) 25th Percentile 27.0 25.0 Median 37.0 37.075th Percentile 49.0 49.0 Minimum, 6.0, 58.0 10.0, 60.0 Maximum 5 (Week4) N 73 71 76 74 Mean (SD) 37.4 (13.1) 1.3 (11.5) 39.3 (12.7) 3.5 (10.5)25th Percentile 28.0 −5.0 31.5 −2.0 Median 38.0 1.0 40.0 3.0 75thPercentile 48.0 8.0 50.0 10.0 Minimum, 11.0, 59.0 −38.0, 36.0 6.0, 59.0−26.0, 41.0 Maximum p-value vs. 0.2044 placebo [1] Least Squares 1.3(1.2) 3.4 (1.2) Means (SE) [2] p-value vs. 0.1081 placebo [2] 6 (EOS) N69 67 74 72 Mean (SD) 38.7 (11.7) 1.2 (8.9) 40.6 (12.6) 3.8 (10.7) 25thPercentile 28.0 −5.0 31.0 −2.5 Median 40.0 1.0 41.5 3.0 75th Percentile47.0 5.0 51.0 10.0 Minimum, 17.0, 60.0 −22.0, 25.0 8.0, 59.0 −24.0, 39.0Maximum p-value vs. 0.2733 placebo [1] Least Squares 1.2 (1.1) 3.3 (1.1)Means (SE) [2] p-value vs. 0.0753 placebo [2] Pain and 3 (Baseline) N 7375 Other Symptoms Mean (SD) 63.5 (20.7) 62.2 (22.6) 25th Percentile 48.047.0 Median 65.0 62.0 75th Percentile 79.0 81.0 Minimum, 21.0, 99.019.0, 110.0 Maximum 5 (Week 4) N 73 71 76 74 Mean (SD) 63.3 (20.5) 1.0(19.2) 68.5 (21.1) 6.9 (16.4) 25th Percentile 46.0 −11.0 53.5 1.0 Median64.0 0.0 69.7 6.0 75th Percentile 79.0 10.0 86.0 13.0 Minimum, 25.0,106.0 −55.0, 55.0 14.0, 101.0 −46.0, 50.0 Maximum p-value vs. 0.0681placebo [1] Least Squares 1.0 (1.9) 6.6 (1.9) Means (SE) [2] p-value vs.0.0182 placebo [2] 6 (EOS) N 69 67 74 72 Mean (SD) 67.3 (19.7) 3.4(15.0) 70.0 (21.0) 7.0 (18.5) 25th Percentile 51.0 −8.0 55.0 −5.0 Median64.0 2.0 71.0 7.5 75th Percentile 83.0 12.0 88.0 17.0 Minimum, 31.0,108.0 −28.0, 52.0 27.0, 107.0 −44.0, 52.7 Maximum p-value vs. 0.3068placebo [1] Least Squares 3.2 (1.8) 6.1 (1.8) Means (SE) [2] p-value vs.0.1317 placebo [2][1] The pairwise comparison is a one-sided test performed using an ANOVAmodel, using the MIXED procedure with treatment and site as fixedeffects.[2] The pairwise comparison is a one-sided test performed using anANCOVA model, using the MIXED procedure, with treatment and site asfixed effects and baseline as the covariate.

Eszopiclone also had a significant effect on change from baseline to theend of study in the Subject Pain Severity Assessment. See Table 2. TABLE2 Subject Pain Severity Assessment (Intent-to-Treat Population) PlaceboEszopiclone 3 mg Observed Change from Observed Change from Visit (Week)Statistic Value Baseline Value Baseline 3 (Baseline) N 73 76 Mean (SD)4.9 (2.4) 5.1 (2.3) 25th Percentile 3.0 3.0 Median 5.0 5.0 75thPercentile 7.0 7.0 Minimum, Maximum 0.0, 10.0 0.0, 10.0 5 (Week 4) N 7473 76 76 Mean (SD) 5.1 (2.7) 0.3 (2.1) 4.6 (2.7) −0.5 (2.6) 25thPercentile 3.0 −1.0 2.5 −2.0 Median 6.0 0.0 5.0 −1.0 75th Percentile 7.01.0 7.0 0.5 Minimum, Maximum 1.0, 10.0 −6.0, 6.0 0.0, 10.0 −7.0, 7.0p-value vs. placebo [1] 0.1121 Least Squares Means 0.2 (0.3) −0.5 (0.2)(SE) [2] p-value vs. placebo [2] 0.0228[1] The pairwise comparison is a one-sided test performed using an ANOVAmodel, using the MIXED procedure with treatment and site as fixedeffects.[2] The pairwise comparison is a one-sided test performed using anANCOVA model, using the MIXED procedure, with treatment and site asfixed effects and baseline as the covariate.The pain assessment was made by subjects in response to a question “Howmuch pain have you had because of your illness in the past week?” Theseverity of pain was rated by each subject on a scale from 0 to 10 withno pain at value of 0 and severe pain at value of 10.

The contents of each of the references cited herein, including thecontents of the references cited within the primary references, areherein incorporated by reference in their entirety. The invention beingthus described, it is apparent that the same can be varied in many ways.Such variations are not to be regarded as a departure from the spiritand scope of the present invention, and all such modifications andequivalents as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

1. A method for treating low-level, chronic pain comprisingadministering to a patient a therapeutically effective amount ofeszopiclone.
 2. A method according to claim 1 wherein said pain isneuropathic pain or pain associated with rheumatoid arthritis,osteoarthritis, muscle spasm, spasticity or fibromyalgia.
 3. A methodfor treating fatigue associated with pain comprising administering to apatient a therapeutically effective amount of eszopiclone.
 4. A methodaccording to any of claims 1 to 3 wherein said eszopiclone isadministered parenterally, transdermally, orally or by inhalation.
 5. Amethod according to any of claims 1 to 3 wherein said eszopiclone isadministered in an amount of 0.5 mg to 15 mg per day.
 6. A methodaccording to claim 5 wherein said eszopiclone is administered in anamount chosen from of 0.5 mg, 1.0 mg, 2.0 mg and 3.0 mg per dosage.